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30

Aug

2016

Implanting Liver Organoids to Generate Functional Liver Tissue

In the research linked here, publicity materials and open access paper (PDF only, alas), the authors report on the generation of liver organoids that spur the growth of functional liver tissue when implanted into mice. The degree of functional gain is small, but this is one step upon a longer road. This is very much the age of organoids, a period of tissue engineering in which researchers are successfully establishing the methodologies needed to grow functional organ tissue, but are still very limited by the inability to reliably generate blood vessel networks. Thus the created tissues largely work as they are intended to, but are tiny in size: any bigger and the inner cells could not be supplied with sufficient oxygen and nutrients.

Organoids are useful in research, as a much more cost effective way of performing drug assessments, for example, or a way to generate dysfunctional tissues that mimic disease processes more accurately than animal models. The utility doesn't stop there, however. For those organs that operate largely as filters or chemical factories, and where the present large-scale structure and shape is not strictly necessary for correct function, it is a very plausible near-term goal to grow organoids from the patient's own cells and implant them inside or alongside the existing organ. Either the implanted organoids contribute to organ function, helping to rescue the patient from organ damage, or in the best of scenarios they will encourage regrowth and regeneration as well - a sort of hybrid half-way point between a cell therapy and an organ transplant. I predict that we'll be seeing ever more of this sort of use of organoids, and that usage will accelerate as the blood vessel challenge continues to go unsolved.

The liver is the most regenerative of organs in mammals. Even we humans are capable of regrowing lost sections of liver under favorable circumstances. Further, many of the liver's activities are independent of its location and shape - a selection of biochemical and cellular factory processes such as detoxification that only require access to the bloodstream. These points make the liver an excellent place to start building regenerative therapies, given the present state of biotechnology. There is certainly a need for these therapies: at the present time comparatively little can be done to compensate for the loss of the liver's activities as the organ fails with age.

Liver transplantation is the only effective treatment for end-stage liver disease, but scarcity of available organs and the need for lifelong immunosuppressive medication make this treatment challenging. Alternate approaches that have been investigated include significant limitations. For example, conventional liver cell transplantation requires scarce donor liver and a perfusion protocol that wastes many cells. This type of cell transplant typically lasts less than one year, with most patients ultimately requiring a liver transplant. Human-induced pluripotent stem (iPS) cells are another possibility but, so far, iPS cells have remained immature rather than developing into functional and proliferative liver cells, called hepatocytes. There continues to be a need for a durable treatment, particularly one that could eliminate the need for immunosuppression.

"Based on the success in my lab generating tissue-engineered intestine and other cell types, we hypothesized that by modifying the protocol used to generate intestine, we would be able to develop liver organoid units that could generate functional tissue-engineered liver when transplanted." The research team generated liver organoid units (LOU) from human and mouse liver and implanted both varieties of LOU into murine models. Tissue-engineered liver developed from the human and mouse LOU, with key cell types required for hepatic function including bile ducts and blood vessels, hepatocytes, stellate cells and endothelial cells. However, the cellular organization differed from native liver tissue. Human albumin, the main type of protein in the blood, was detected in the host mouse serum, indicating in vivo secretory function from the human-derived tissue-engineered liver. In a mouse model of liver failure, tissue-engineered liver was able to provide some hepatic function. In addition, the hepatocytes proliferated in the tissue-engineered liver.

Liver disease affects large numbers of patients, yet there are limited treatments available to replace absent or ineffective cellular function of this crucial organ. Donor scarcity and the necessity for immunosuppression limit one effective therapy, orthotopic liver transplantation. But in some conditions such as inborn errors of metabolism or transient states of liver insufficiency, patients may be salvaged by providing partial quantities of functional liver tissue. After transplanting multicellular liver organoid units composed of a heterogeneous cellular population that includes adult stem and progenitor cells, both mouse and human tissue-engineered liver (TELi) form in vivo.

TELi contains normal liver components such as hepatocytes with albumin expression, CK19-expressing bile ducts and vascular structures with α-smooth muscle actin expression, desmin-expressing stellate cells, and CD31-expressing endothelial cells. At 4 weeks, TELi contains proliferating albumin-expressing cells and identification of β2-microglobulin-expressing cells demonstrates that the majority of human TELi is composed of transplanted human cells. Human albumin is detected in the host mouse serum, indicating in vivo secretory function. Analysis of mouse serum after debrisoquine administration is followed by a significant increase in the level of the human metabolite, 4-OH-debrisoquine, which supports the metabolic and xenobiotic capability of human TELi in vivo. Thus implanted TELi grew in a mouse model of inducible liver failure.

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